Traditional approaches to the treatment of diseases such as cancer have included surgery, radiation, chemotherapy, antibiotics or combination therapies. However, such therapies have not proven effective against a majority of these indications. Development of alternate remedies for preventing and/or treating such human diseases is crucial. In recent years immunotherapy and gene therapy approaches utilizing antibodies and T-lymphocytes have emerged as new and promising methods for treating human disease.
One such approach to treatment has included the use of antibodies for targeting of therapeutic or diagnostic agents to particular targets. Numerous groups have made developments revolving around the use of antibodies as a targeting agent. Such developments have included construction of antibody fusion proteins and antibody conjugate molecules linking antibodies to various effector molecules, including radioactive molecules, chemotherapeutics agents, toxins, and additional bioactive proteins. Therapeutics or diagnostics developed using such molecules are designed to cause a particular effect which is targeted by the linked antibody.
Just as antibodies have been developed as therapeutics, additional primary effectors of the immune system, T cell receptors (TCR), have unique advantages as a platform for developing therapeutics. While antibodies are limited to recognition of pathogens in the blood and extracellular spaces or to protein targets on the cell surface, T cell receptors can recognize antigens displayed with MHC molecules on the surfaces of cells (including antigens derived from intracellular proteins). Depending on the subtype of T cells that recognize displayed antigen and become activated, T cell receptors and T cells harboring T cell receptors can participate in controlling various immune responses. For instance, T cells are involved in regulation of the humoral immune response through induction of differentiation of B cells into antibody producing cells. In addition, activated T cells act to initiate cell-mediated immune responses. Thus, T cell receptors can recognize additional targets not available to antibodies.
A T cell response is modulated by antigen binding to a T cell receptor molecule. One type of TCR is a membrane bound heterodimer consisting of an α chain and a β chain resembling an immunoglobin variable (V) and constant (C) region. The TCR α chain includes a covalently linked Vα and Cα chain, whereas the β chain includes a Vβ chain covalently linked to a Cβ chain. The Vα and Vβ chains form a pocket or cleft that can bind a superantigen or antigen in the context of a major histocompatibility complex (MHC) (known in humans as an HLA complex). See generally Davis, Ann. Rev. of Immunology 3: 537 (1985); Fundamental Immunology 3rd Ed., W. Paul Ed. Raven Press LTD. New York (1993).
The TCR is believed to play an important role in the development and function of the immune system. For example, the TCR has been reported to mediate cell killing, increase B cell proliferation, and impact the development and severity of various disorders including cancer, allergies, viral infections and autoimmune disorders.
Human p53 has been reported to be a tumor suppressor protein and peptide epitopes from p53 are presented by particular class I MHC molecules. p53 has been further reported to be a candidate for a broad-spectrum, tumor-associated cytotoxic T-cell (CTL) target. See, e.g., Theobald, M. et. al. (1995) PNAS (USA) 92: 11993 and references cited therein.
There is recognition that abnormal forms of the human p53 protein are associated with a wide variety of cancers. One belief is that the abnormal or mutated version overrides the protective features of normal (wild-type) p53 protein. See, e.g., Levine, A. J. et. al. (1991) Nature (London) 351: 453.
Human class I molecules that recognize and specifically bind peptides derived from human p53 protein have been described. One such molecule is HLA-A2.1. See, Theobald, M. et. al., supra.
It would be desirable to have TCR molecules that recognize and bind peptides derived from the human p53 protein. It would be especially desirable to have heterodimeric and single chain TCR molecules that specifically bind sequence spanning about amino acid positions 264 to 272 of the human p53 protein.